ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

摘要

We have developed several novel small molecule inhibitors of BCR-ABL that inhibit the proliferation and induce apoptosis of CML cell lines that express the WT or the T315I mutant form of BCR-ABL. These compounds readily induced the down-regulation of BCR-ABL auto-phosphorylation and STAT-5 phosphorylation. Using ON044580 as the lead compound, we have carried out detailed structure/function studies which demonstrate that ON044580 inhibits the kinase activity of both the wild-type and T315I mutant form of BCR-ABL. In addition, this compound inhibited the kinase activity of WT and V617F mutant forms of JAK2 and induce apoptosis of leukemic cell lines that express the V617F mutant form of JAK2. We show that ON044850 destroys the Bcr-Abl/Jak2 protein Network, which is a large multi-component signaling structure maintained in an active state by members of the HSP90 chaperone complex. ON044850 causes reduction of STAT3 levels leading to reduced expression of HSP90. Thus, our results suggest that targeting Jak2 and Bcr-Abl kinases is an effective way to destabilize Bcr-Abl and its network complex, which leads to the onset of apoptosis in IM-sensitive and -resistant Bcr-Abl+ cells.